Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China.
Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China.
Food Chem Toxicol. 2024 Mar;185:114475. doi: 10.1016/j.fct.2024.114475. Epub 2024 Jan 28.
Chlormequat chloride (CCC), as a widely used plant growth regulator, can cause impaired sperm quality and decreased testosterone synthesis in pubertal rats, but the underlying mechanism remains unclear. The purpose of this study was to elucidate the toxicokinetics and tissue distribution of CCC, as well as the possible mechanism of CCC-induced impairment in sperm quality. The concentration of CCC reached its peak 1 h after a single dose (200 mg/kg·bw) administration in mice plasma, and a bimodal phenomenon appeared in the testes, liver, and epididymis. In vivo, 200 mg/kg CCC caused testicular damage and impaired sperm quality in pubertal mice, and the expression of p-tyrosine and GSK3α decreased in cauda epididymidis, sperm and testes. CCC also caused the down-regulation of AKAP4 and the up-regulation of calmodulin (CaM), and activated the PI3K/AKT signaling pathway in the testes. In vitro, CCC reduced the levels of p-tyrosine, AKAP4 and GSK3α, increased the level of CaM and activated the PI3K/AKT signaling pathway in GC-1 cells. CaM antagonist (W-7 hydrochloride) and PI3K inhibitor (LY294002) can effectively improve the expression of GSK3α and AKAP4 by suppressing the PI3K/AKT signaling pathway in GC-1 cells treated with CCC. It was indicated that CCC induced impairment in sperm quality might be partially related to the activation of PI3K/AKT signaling pathway mediated by CaM.
氯化氯代胆碱（CCC）作为一种广泛使用的植物生长调节剂，可导致青春期大鼠精子质量受损和睾酮合成减少，但潜在机制尚不清楚。本研究旨在阐明 CCC 的毒代动力学和组织分布，以及 CCC 引起精子质量受损的可能机制。
在小鼠血浆中，单次给药（200mg/kg·bw）后 1 小时 CCC 浓度达到峰值，睾丸、肝脏和附睾出现双峰现象。体内，200mg/kg CCC 导致青春期小鼠睾丸损伤和精子质量受损，尾部附睾中 p-酪氨酸和 GSK3α 的表达降低，精子和睾丸中亦然。CCC 还导致 AKAP4 下调和钙调蛋白（CaM）上调，并激活睾丸中的 PI3K/AKT 信号通路。
体外，CCC 降低 GC-1 细胞中 p-酪氨酸、AKAP4 和 GSK3α 的水平，增加 CaM 的水平，并激活 CCC 处理的 GC-1 细胞中的 PI3K/AKT 信号通路。钙调蛋白拮抗剂（W-7 盐酸盐）和 PI3K 抑制剂（LY294002）可通过抑制 PI3K/AKT 信号通路有效改善 CCC 处理的 GC-1 细胞中 GSK3α 和 AKAP4 的表达。
这表明 CCC 引起的精子质量受损可能部分与 CaM 介导的 PI3K/AKT 信号通路的激活有关。
